Why Doctors Still Don't Know Which Heart Drugs Work Best

I'd like to let you in on a little secret in medicine. We know a lot less than you might think about the effects of medications and, in particular, how they compare with each other. Last week an article in JAMA, one of the premier medical journals, reminded us of this problem.

Angiotensin II receptor blockers (often known as ARBs) are some of the best selling drugs for treating high blood pressure, heart failure, and kidney disease from diabetes. This class of drug blocks the effect of a hormone, angiotensin II, that can exacerbate these conditions.

These drugs go by the names losartan (Cozaar from Merck), candesartan (Atacand from AstraZeneca), valsartan (Diovan from Novartis), irbesartan (Avapro from Sanofi-Aventis and Bristol-Myers Squibb), telmisartan (Micardis), eprosartan (Teveten), and olmesartan (Benicar). If your doctor thought you should use an ARB and you agreed, which one should you use?

Basic pharmacology studies tell us that they are not the same. Although all bind the receptor for angiotensin II, and thus block the effect of the hormone, they vary in their fit with the receptor, how long they last in the body, how they are handled by the body and what doses should be taken. They are different. And yet, what is lacking in medical research are head to head comparisons. We don't know which one is the best one - whether the effects are the same - whether the safety is the same - and whether certain patients are better off with one of the ARBs over another. The choice may ultimately depend on marketing, price, availability by the formulary, or some other consideration.

Last week's paper, out of Sweden, used a national registry of patients with heart failure to compare the effects of these drugs. They identified 2639 patients taking candesartan and 2500 taking losartan (there were not enough people taking the other ARBs to make it worthwhile to compare them). Their bottom line was that patients taking Merck's losartan had almost a 50% higher risk of dying compared with those taking AstraZeneca's candesartan.

I think most doctors would be surprised that the drugs in the class might not have similar effect on patients. We are lulled into the belief that class effects dominate. So doctors are prescribing these medications interchangeably - the guidelines make an assumption that there is no difference in the effect of the drugs within the class. Now this study indicates the possibility of an almost 50% higher risk of death when losartan is chosen over candesartan.

Now the study has limitations. Although the investigators try to adjust for differences in the group, the fact that it was not a randomized study means that it is possible that the difference is a result of doctors using candesartan in healthier patients. There is no reason why that might happen - but they did report that the candesartan group was a bit younger than the losartan group (they adjusted for that and other factors). The investigators were also reluctant to say that their study should influence doctors - writing that there is a need for further studies to validate this result.

And yet, what are we to do? At the least the study indicates the urgent need for head to head studies which can reveal differences within a class. We already have evidence that it is a flawed assumption in the area of statins, diabetes medications, anti-inflammatory drugs, and others.

The drug industry has little impetus to conduct such head-to-head studies--it is all risk without benefit for them. Head-to-head comparative treatment studies also haven't been a focus of the National Institutes of Health which tends toward basic research.

Increasingly, there is a call for these direct comparison studies under the heading of comparative effectiveness. But so far there are not enough of them to even begin to address the gaps in our knowledge.

The absence of head to head comparisons leave companies to compete on marketing and speculation about the advantages of their product. It would be better for them to compete on the science - and evidence of the superiority of their product to the alternatives in the field. Everyday practice cannot reveal these differences - only direct comparisons.

And for those of you on losartan for the treatment of heart failure... the uncertainty will persist. This finding will cause much discomfort among those who know about it. Since the choice between ARBs is usually a toss-up, I will lean toward recommending candesartan until more information becomes available. This study makes it a little more likely that there are differences that favor that drug over losartan. But I will not be surprised to learn that there is more to this story.